Dissertation
Dissertation > Medicine, health > Pharmacy > Drug basic science > Medicinal Chemistry

Study on Asymmetric Michael Addition Reactions of Chalcones

Author LiuYuLong
Tutor HeZuo
School Fourth Military Medical University
Course Medicinal Chemistry
Keywords Chalcones Michael addition Organocatalyst thiourea Cinchona alkaloids
CLC R914
Type Master's thesis
Year 2013
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Chalcones are important intermediates in organic synthesis and drug synthesis. TheMichael addition reaction is one of important ways for carbon (atom)-carbon (atoms) andcarbon (atom)-hetero (atom) bond formation, and its asymmetric version is an effectivetool to get chiral derivatives of chalcones. Organo-catalyzed Michael addition has anunique advantage because it can be conducted easily without employing expensive andresidual metal as the active center.In this thesis, a series of chiral thiourea catalysts are synthesized from naturalcinchona alkaloids and chiral amino acids. This kind of catalysts has multiple hydrogenbonding sites and a basic tertiary amine group in their moleculars. Through hydrogenbonding effect, the nucleophile and electrophilic in a reaction can be actived by thioureamoiety and tertiary amine group, respectively. In this thesis, study on the application oftertiary amine-thiourea catalyst in the asymmetric Michael addition reaction of chalconeshas been carried out. The main content of the research includes the following:1. Synthesis of13bifunctional thiourea catalysts from natural cinchona alkaloids and chiral amino acids (amino alcohol) through simple synthesis steps. Their moleculestructures are confirmed by IR,1H NMR,13C NMR, LC-MS and HRMS.2. The application of these bifunctional thiourea catalysts in asymmetric Michaeladdition of diethyl malonate to chalcones. R-isomers are gained in high yield (up to99%)and enantioselectivity (up to97%) when10mol%55g is employed as catalyst. S-isomersare gained in high yield (up to99%) and high enantioselectivity (up to96%ee) with10mol%55m as catalyst.15chalcones ware tested, and among the adducts,67b,67d,67f,67g,67i,67k,67l,67m and67o are new substances, their molecule structures areconfirmed by IR,1H NMR,13C NMR, LC-MS and HRMS.3. The application of these bifunctional thiourea catalysts in asymmetric Michaeladdition of nitromethane/α-cyano-ethyl acetate to chalcone has also been investigated. Inasymmetric Michael addition reaction of nitromethane to chalcone,55e shows to be apromising catalyst and asymmetric adduct is obtained in moderate yield (69%) and goodenantioselectivity (86%ee).4. In asymmetric Michael addition reaction of α-cyano-ethyl acetate to chalcone,55jshows to be a promising catalyst and asymmetric adduct is obtained in low yield (69%),low diastereoselectivity (syn/anti65/35dr) and moderate enantioselectivity (70%ee foreach isomer). Optimizing other reaction conditions is on going in our laboratory.The results show that: The bifunctional chiral thiourea organocatalysts bearingmultiple hydrogen-bonding donors derived from natural cinchona alkaloids and chiralamino acids (amino alcohol) exhibit excellent catalytic activities in the asymmetricMichael addition reaction of diethyl malonate to chalcones. By changing the compositionof cinchona alkaloids and chiral amino acids (amino alcohol) both single isomer productscan be obtained in high yield and high enantioselectivity, respectively. The bifunctionalchiral thiourea organiccatalysts also show promising catalytic activities in asymmetricMichael addition reaction of nitromethane/α-cyano-ethyl acetate to chalcones.

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